Formulations of pimavanserin

ABSTRACT

Provided herein are capsules containing pimavanserin, processes for manufacturing said capsule, and pharmaceutical compositions containing pimavanserin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/363,378, filed on Mar. 25, 2019, which is a continuation ofInternational Patent Application No. PCT/US2018/048096, filed on Aug.27, 2018, which claims priority to and the benefit of U.S. ProvisionalPatent Application No. 62/552,300, filed Aug. 30, 2017, and SwedishPatent Application No. 1730232-4, filed Sep. 1, 2017.

FIELD

Provided herein are capsules of pimavanserin and pharmaceuticallyacceptable salts thereof, as well as pharmaceutical compositions ofpimavanserin and methods for manufacturing the capsules.

BACKGROUND

Pimavanserin, the active component in Nuplazid®, is approved fortreatment of hallucinations and delusions associated with Parkinson'sdisease psychosis at a dose of 34 mg, taken as two 17 mg tablets once aday. The tablets are immediate release, film-coated tablet containing 20mg of pimavanserin tartrate, which is equivalent to 17 mg ofpimavanserin free base. Inactive ingredients include pregelatinizedstarch, magnesium stearate, and microcrystalline cellulose.Additionally, the following inactive ingredients are present ascomponents of the film coat: hypromellose, talc, titanium dioxide,polyethylene glycol, and saccharin sodium.

Patients suffering from neurodegenerative diseases, such as Parkinson'sdisease are at a risk of non-compliance when administered a drug of toolarge size, or if taken as more than one tablet per day as said patientsoften have difficulty swallowing. Formulations of pimavanserin aredescribed in WO 2007/133802. Pimavanserin is currently approved andadministered as tablets containing 20 mg pimavanserin tartrate(equivalent to 17 mg pimavanserin), taken as two tablets once a day.Each with a total 150 mg tablet weight before film coating, i.e. totalweight per dose is 300 mg (equivalent to 34 mg pimavanserin). In orderto simplify administration and patient compliance of pimavanserin itwould be advantageous to administer pimavanserin as a single dose.

Improved manufacturing processes for single unit dose forms,particularly for smaller sized single unit dosage forms, for oraladministration of a therapeutic quantity of pimavanserin are critical.The physical properties of pimavanserin, e.g. bulk density and flow,when prepared in a tablet form requires, e.g. binders and other agentsthat increase the finished dosage size. Pimavanserin manufacturedfollowing conventional techniques has low bulk density and poorflowability and a tendency to clump, which will adversely impactreproducibility and quantitative accurate filling of capsules during themanufacturing process.

Consequently there is a need to improve the properties of pimavanserinallowing dosing of the daily therapeutic dose as a singleadministration.

SUMMARY

Provided herein are capsules comprising 5-34 mg pimavanserin (equivalentto 6-40 mg pimavanserin tartrate), or a pharmaceutically acceptable saltthereof

Provided herein are also pharmaceutical compositions consisting of 5-34mg pimavanserin or a pharmaceutically acceptable salt thereof, a fillerand a lubricant.

Provided herein are also processes for manufacturing a capsulecomprising 5-34 mg pimavanserin or a pharmaceutically acceptable saltthereof comprising: adding water to pimavanserin or a pharmaceuticallyacceptable salt thereof, and granulating pimavanserin or apharmaceutically acceptable salt thereof with the water; controlling theimpeller speed and/or amperage; drying the granulated pimavanserin or apharmaceutically acceptable salt thereof; sizing the dried granulatedpimavanserin or a pharmaceutically acceptable salt thereof; blending thedried and granulated pimavanserin or a pharmaceutically acceptable saltthereof and one or more filler; encapsulating the blended pimavanserincomposition in a capsule of size 3 or 4.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a table disclosing specifications of capsule sizes,commercially available.

FIG. 2 schematically discloses a process flow chart for pimavanseringranulation.

FIG. 3 schematically discloses a process flow chart for encapsulatingpimavanserin granulation

FIG. 4 shows a particle size distribution diagram of pimavanserintartrate.

FIG. 5 shows a particle size distribution diagram of granulatedpimavanserin.

DETAILED DESCRIPTION

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety. In the event that there are a plurality of definitions for aterm herein, those in this section prevail unless stated otherwise.

As used herein, “pharmaceutical composition” refers to a composition ofone or more active pharmaceutical ingredient(s) alone, or administeredwith other chemical components, such as diluents, binders, lubricants,pharmaceutical flow agents, and/or other excipients, e.g. for forming aunit dose, such as a tablet, a capsule etc.

As used herein, “physiologically acceptable” defines a diluent, binder,or excipient that does not abrogate the biological activity andproperties of the pharmaceutically active compound.

As used herein, “pharmaceutically acceptable salt” refers to a salt of acompound that does not abrogate the biological activity and propertiesof the compound. Pharmaceutical salts can be obtained by reaction of acompound disclosed herein with an acid or base. Base-formed saltsinclude, without limitation, ammonium salt (NH₄ ⁺); alkali metal, suchas, without limitation, sodium or potassium, salts; alkaline earth, suchas, without limitation, calcium or magnesium, salts; salts of organicbases such as, without limitation, dicyclohexylamine, piperidine,piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine,ethylenediamine, tris(hydroxymethyl)methylamine; and salts with theamino group of amino acids such as, without limitation, arginine andlysine. Useful acid-based salts include, without limitation, acetates,adipates, aspartates, ascorbates, benzoates, butyrates, caparate,caproate, caprylate, camsylates, citrates, decanoates, formates,fumarates, gluconates, glutarate, glycolates, hexanoates, laurates,lactates, maleates, nitrates, oleates, oxalates, octanoates,propanoates, palmitates, phosphates, sebacates, succinates, stearates,sulfates, sulfonates, such as methanesulfonates, ethanesulfonates,p-toluenesulfonates, salicylates, tartrates, and tosylates.

Pharmaceutically acceptable solvates and hydrates are complexes of acompound with one or more solvent of water molecules, or 0.5 to about100, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4,solvent or water molecules.

As used herein, to “modulate” the activity of a receptor means either toactivate it, i.e., to increase its cellular function over the base levelmeasured in the particular environment in which it is found, ordeactivate it, i.e., decrease its cellular function to less than themeasured base level in the environment in which it is found and/orrender it unable to perform its cellular function at all, even in thepresence of a natural binding partner. A natural binding partner is anendogenous molecule that is an agonist for the receptor.

An “agonist” is defined as a compound that increases the basal activityof a receptor (e.g. signal transduction mediated by the receptor).

As used herein, “partial agonist” refers to a compound that has anaffinity for a receptor but, unlike an agonist, when bound to thereceptor it elicits only a fractional degree of the pharmacologicalresponse normally associated with the receptor even if a large number ofreceptors are occupied by the compound.

An “inverse agonist” is defined as a compound, which reduces, orsuppresses the basal activity of a receptor, such that the compound isnot technically an antagonist but, rather, is an agonist with negativeintrinsic activity.

As used herein, “antagonist” refers to a compound that binds to areceptor to form a complex that does not give rise to any response, asif the receptor was unoccupied. An antagonist attenuates the action ofan agonist on a receptor. An antagonist may bind reversibly orirreversibly, effectively eliminating the activity of the receptorpermanently or at least until the antagonist is metabolized ordissociates or is otherwise removed by a physical or biological process.

As used herein, a “subject” refers to an animal that is the object oftreatment, observation or experiment. “Animal” includes cold- andwarm-blooded vertebrates and invertebrates such as birds, fish,shellfish, reptiles and, in particular, mammals. “Mammal” includes,without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep;goats; cows; horses; primates, such as monkeys, chimpanzees, and apes,and, in particular, humans.

As used herein, an “excipient” refers to an inactive ingredient that isadded to a pharmaceutical composition to provide, without limitation,bulk, consistency, stability, binding ability, lubrication,disintegrating ability, etc., to the composition. A “diluent” is a typeof excipient.

As used herein, a “diluent”, “bulking agent” and “filler” refer to aningredient (excipient) in a pharmaceutical composition that lackspharmacological activity but may be pharmaceutically necessary ordesirable, e.g. to enhance or improve the properties of thepharmaceutical blend for manufacturing or physiological purposes. Forexample, a diluent or filler may be used to increase the bulk of apotent drug whose mass is too small for manufacture or administration.

As used herein, a “binder” is an excipient holding the ingredientstogether, and forming granules or tablets with required mechanicalstrength, and may give volume to the formulation. Specific examples ofbinders are mono-, di-, and poly-saccharides and derivatives thereof;sugar alcohols such as xylitol, sorbitol or maltitol; protein, such as;synthetic polymers, such as polyvinylpyrrolidone (PVP), polyethyleneglycol (PEG). Binders are classified according to their application,e.g. solution binders are dissolved in a solvent (for example water oralcohol may be used in wet granulation processes). Examples includegelatin, cellulose, cellulose derivatives, polyvinylpyrrolidone, starch,sucrose and polyethylene glycol. Dry binders are added to the powderblend, either after a wet granulation step, or as part of a directpowder compression (DC) formula. Examples include cellulose, methylcellulose, polyvinylpyrrolidone and polyethylene glycol.

As used herein a “lubricant” refers to an excipient which for exampleprevents ingredients and excipients to lump together, and/or sticking tothe capsule filling machine. A lubricant may also ensure that theformation, filing and ejection of the capsule can occur, for example bylowering friction. Examples of lubricants are talc, silicon dioxide(silica), fatty acids or fatty acid salts, such as magnesium stearate,sodium stearate fumarate, stearic acid, etc.

As used herein a “disintegrant” refers to an excipient whichdisintegrate a pharmaceutical preparation on contact with an aqueousfluid.

As used herein, “coadministration” of pharmacologically active compoundsrefers to the delivery of two or more separate chemical entities,whether in vitro or in vivo. Coadministration means the simultaneousdelivery of separate agents; the simultaneous delivery of a mixture ofagents; as well as the delivery of one agent followed by delivery of asecond agent or additional agents. Agents that are coadministered aretypically intended to work in conjunction with each other.

The term “an effective amount” as used herein means an amount of activecompound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician,which includes alleviation or palliation of the symptoms of the diseasebeing treated.

The terms screen, screening, delump, delumping, dry milling, and sizingare used interchangeably herein. These terms refer to separationaccording to size.

The term “granulation” as used herein, and as conventionally used in thepharmaceutical industry, refers to the act or process in which primarypowder particles are made to adhere to form larger, multiparticleentities called granules. Granules may for example be formed collectingparticles together by creating mechanical bonds between them, e.g. bycompression or by using a binder. Granulation is extensively used in themanufacturing of tablets and capsules.

The terms “granulated pimavanserin” and “pimavanserin granulation” areused interchangeably herein.

Generally a granulation process combines one or more particles and formsa granule that will allow tableting or the encapsulation process to bewithin required limits. The granulation process can be made predictableand repeatable. The granulation can be performed in a variety ofequipment such as, but not limited to, low shear, high sheargranulators, fluid bed granulator, roller compactor, and slugger.

The term “blending” refers to the mixing of pharmaceutical ingredientsto form a mixture of the ingredients, e.g. active pharmaceuticalingredient (API) and diluent, as defined by pharmaceuticalspecifications in the compendial references using a variety of equipmentsuch as, but not limited to, “V”-blenders, bin-blenders, cone-blenders.

The term “encapsulation” refers to a range of techniques used to enclosemedicines in a shell, e.g. a two-piece capsule, such as a two-piece hardshell capsule. The capsule referred to herein may be taken orally.Capsules may be designed with a telescoping cap and body manufacturedfrom e.g. gelatin or cellulose.

Compounds

Pimavanserin, which is also known asN-(1-methylpiperidin-4-yl)-N-(4-fluorophenylmethyl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide,N-[(4-fluorophenyl)methyl]-N-(1-methyl-4-piperidinyl)-N′-[[4-(2-methylpropoxy)phenyl]methyl]-urea,1-(4-fluorobenzyl)-1-(1-methylpiperidin-4-yl)-3-[4-(2-methylpropoxy)benzyl]urea,or ACP-103. Pimavanserin commonly is administered as pimavanserintartrate and has the structure of Formula (I):

Pimavanserin has previously been synthesized according to the methoddisclosed in Scheme I.

Alternative methods for preparing pimavanserin are disclosed inWO017/015272, which is incorporated herein by reference in its entirety.

Pimavanserin and methods for its use are described in U.S. Pat. Nos.7,601,740; 7,659,285; 7,713,995; 7,732,462; 7,994,193 and 8,008,323, theentirety of each of which is hereby incorporated by reference.Pimavanserin can be obtained in a number of salt and crystalline forms.Exemplary pharmaceutically acceptable salts include the tartrate,hemi-tartrate, citrate, fumarate, maleate, malate, phosphate, succinate,sulphate, and edisylate (ethanedisulfonate) salts. Pimavanserin saltsincluding the aforementioned ions, among others, are described in U.S.Patent Publication No. 2006-0111399, filed Sep. 26, 2005, the entiretyof which is incorporated herein by reference. In an embodiment providedherein, pimavanserin is the tartrate salt of pimavanserin. Severalcrystalline forms of the tartrate salt of pimavanserin have beendescribed in U.S. Patent Publication No. 2006-0106063, filed Sep. 26,2006, the entirety of which is incorporated herein by reference. Seealso U.S. Pat. Nos. 7,732,615; 7,795,547; 7,790,899; 7,868,176, theentirety of each of which is incorporated herein by reference. In anembodiment provided herein, pimavanserin is the crystalline form of thetartrate salt of pimavanserin Form A. In another embodiment,pimavanserin is the crystalline form of the tartrate salt ofpimavanserin Form C. Pimavanserin (including, for example, the tartratesalt) may be formulated into tablets, such as is described in U.S.Patent Publication Nos. 2007-0260064, filed May 15, 2007 and2007-0264330, filed May 15, 2007, each of which are incorporated hereinby reference in their entireties.

The pharmacological activity of pimavanserin has been previouslyreported. See U.S. Patent Publication Nos. 2004/0213816 and2009/0053329, the entirety of each of which is hereby incorporated byreference. Pimavanserin is active in a number of models thought to bepredictive of antipsychotic activity such as DOI((±)-2,5-dimethoxy-4-iodoamphetamine, a serotonin agonist) induced headtwitches in the rat and attenuation of hyperactivity in mice induced bythe N-methyl-D-aspartate antagonist MK-801. The compound was effectivein these models at oral doses of 3 and 10 mg/kg.

Suitable routes of administration of pimanvanserin may, for example,include oral, rectal, transmucosal, topical, or intestinaladministration; parenteral delivery, including intramuscular,subcutaneous, intravenous, intramedullary injections, as well asintrathecal, direct intraventricular, intraperitoneal, intranasal, orintraocular injections. The compounds can also be administered insustained or controlled release dosage forms, including depotinjections, osmotic pumps, pills, transdermal (includingelectrotransport) patches, and the like, for prolonged and/or timed,pulsed administration at a predetermined rate. Embodiments providedherein relate to oral administration of a capsule comprisingpimavanserin granulation.

The pharmaceutical compositions described herein comprised in a capsulerefer to compositions prepared by methodologies not conventionally usedin granulation, such as high and low shear granulation, e.g. using lowamounts of water.

For oral administration, the compositions can be formulated readily bycombining the active pharmaceutical ingredient (API) (e.g., pimavanserinor pimavanserin tartrate) with pharmaceutically acceptable binders ordiluents well known in the art. Such binders or diluents enable the APIdisclosed herein to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated.

Provided herein is pimavanserin and pharmaceutically acceptable saltsthereof having altered properties, such as increased bulk density,improved flow, and compressibility allowing the pharmaceuticalmanufacturing of a capsule comprising about 5-34 mg pimavanserin, suchas about 34 mg, which for example may be filled in a size 3 or 4capsule, such as a capsule of size 4.

It has herein been demonstrated that altering the flow and bulk densityof pimavanserin, and compositions comprising pimavanserin using methodsdescribed herein results in a reproducible and quantitatively accuratefilling of small sized capsules (e.g. size 3 or 4 capsules) in a scaledup pharmaceutical manufacturing processes, e.g. for manufacturing ofabout 1,000,000 capsules or more, for example at a speed of 40-90,000capsules per hour.

Pharmaceutical manufacturing as used herein implies certain requirementbeing met such as manufacturing efficiency and economical requirements.Although also product quality and performance are ensured through thedesign of effective and efficient manufacturing processes, product andprocess specifications are based on a mechanistic understanding of howformulation and process factors affect product performance, e.g.variability between batches, assuring continuous real-time quality ofthe product and the materials, e.g. excipients. Additionally, regulatorypolicies and procedures used to meet official requirements such as thoseset out by health authorities, such as EMA (European Medicine agency)and FDA (U.S. Food and Drug Administration) and similar agencies inorder to obtain the required quality of a drug product has an impact onthe pharmaceutical manufacturing. For example, risk-based regulatoryapproaches recognize the level of scientific understanding of howformulation and manufacturing process factors affect product quality andperformance and the capability of process control strategies to preventor mitigate the risk of producing a poor quality product. For example,manual filling of capsules would not be considered relevant by thoseskilled in the art as manual filling of capsules cannot provide highreproducibility at the filling speed required to manufacture batchescontaining more than 100,000 capsules. Consequently those skilled in theart setting out to improve the formulation of an existing activepharmaceutical ingredient (API) for example to improve patientcompliance, are working with tools used within the field ofpharmaceutical manufacturing of small molecules.

Generally when improving the flow of an API (active pharmaceuticalingredient) the fill weight is increased. Increasing the fill weight iscounterproductive to filling a small volume, such as a size 3 or even asize 4 capsule, at the production speeds required, such as 40-90,000capsules per hour.

Disclosed herein are pharmaceutical manufacturing processes forobtaining suitable strength capsules of pimavanserin or apharmaceutically acceptable salt thereof, said process comprisesspraying water to pimavanserin, followed by a granulation process,wherein pimavanserin is granulated without addition of a binder, andblending followed by encapsulation. The particle size distribution,and/or bulk density of the granulated pimavanserin is controlled andmatched to other excipient(s) to improve flow of the composition andassure content uniformity and low variability of the product.Additionally matching of excipient(s) allows reproducibility duringencapsulation of pimavanserin. The matching of physical properties ofAPI and other excipients used herein enables pharmaceuticalmanufacturing, in particular capsule filling (encapsulating the driedpimavanserin granulation in capsules of size 3 or 4) at sufficient speedsuch as more than 40,000 capsules per hour. Matching of API may forexample be done by matching the particle size distribution of the APIand one or more excipient. The bulk density of the API and the one ormore excipients may also be matched.

For example, as shown in table 1, pimavanserin granulation, as obtainedby the pharmaceutical manufacturing described herein vs the native API(active pharmaceutical ingredient (e.g., pimavanserin tartrate),obtained for example as decribed in WO017/015272), the bulk density andthe Can's Index (Carr's Compressibility Index) have been substantiallyaltered which enables the filling of the above mentioned small capsule.Carr's Index compares the difference between the bulk density and tappeddensity of a substance to determine its compressibility. The bulkdensity and the Carr's Index may be determined in accordance withUSP<616> (method for performing Bulk and Tapped Densities, method 1) andUSP<1174> (definition of powder flow) respectively.

TABLE 1 Pimavanserin granulation* Native API Bulk density (g/ml) 0.508(n = 4) 0.294 (n = 2) according to USP <616> Carr's Index 24 (n = 4) 36(n = 2) *final blend as disclosed in the example hereinbelow and intable 2

Table 1 visualizes that filling of a capsule, in particular a capsule ofsize 3 or 4 (capsule volumes of 0.30 and 0.21 ml respectively,approximately 120 mg and 85 mg respectively at a bulk density of 0.5g/ml). As evident from Table 1, native pimavanserin (API) would bechallenging for a size 3 capsule and not possible for a capsule of size4 without improving the bulk density (as comparison 85 mg ofpimavanserin granulation would require about 0.17 ml compared to 0.29 mlfor the native API) and flowability (Carr index is frequently used inpharmaceutical manufacturing as an indication of the flowability of apowder, e.g. 2016 U.S. Pharmacopoeia-National Formulary [USP 35 NF 30]).

In particular, disclosed herein are formulation, granulation, drymilling, blending, and encapsulation of pimavanserin containing novelelements. Salient features are that the known granulation technologyuses atypical parameters to achieve the desired results. Spray rate,atomization and quantity of water are examples of atypical parametersused in combination with wet granulation to obtain the targetedproperties of pimavanserin formulation disclosed herein. For example,pimavanserin has been successfully granulated without the use of binderby spraying, at a controlled rate and under controlled atomizationconditions, a controlled amount of water to pimavanserin during the wetgranulation to provide granulated pimavanserin suitable for furtherprocessing (e.g. drying, blending, etc.) in the pharmaceuticalmanufacturing of capsules containing 5-34 mg pimavanserin, such as 10-34mg capsules of size 3 or 4. Prior to the surprising finding thatpimavanserin could be successfully wet granulated achieving the targetedimporved physical properties (e.g. bulk density) without the addition ofa binder, and by adding a small, such as 2-15% w/w, e.g. 3-10% w/w, 3-8%w/w amount of water to pimavanserin by spraying, many differentgranulation methods were contemplated and tested, and some discussedmore in detail hereinbelow.

In one embodiment, High Shear Granulation (HSG) utilizing a smallquantity of water, such as approximately 3-8% w/w of the dryingredients, under appropriate HSG parameters for atomization, sprayrate, impeller speed, and chopper speed was found to provide therequired improvements to the pimavanserin (API) physical properties,such as increased bulk density, improved flow, and compressibility. Thesmall quantity of water, its application using appropriate wateratomization and/or water application rate are important reasons for theimproved properties of pimavanserin. It has herein been demonstratedthat the atomized spraying of a small amount of water during thegranulation of pimavanserin achieves a wetting of pimavanserin thatprovides a granulated pimavanserin suitable for pharmaceuticalmanufacturing of a capsule, such as a capsule of size 4 comprising 10-34mg pimavanserin. The actual amount of water to be sprayed at thegranulation of pimavanserin may vary from batch to batch (depending onsurrounding factors such as humidity, temperature, exact properties ofthe API batch, etc) but is still consider to be a small amount, e.g.3-10% w/w based on the dry ingredients. The amount of water and thegranulation process disclosed herein is controlled by controlling theimpeller energy to achieve the targeted impeller speed. The appropriateimpeller speed ensures sufficient mixing and controls the growth ofgranules. The specific small amount of water needed for each batch iscontrolled by the power consumption (amperage) of the granulator, i.e.,if the amperage is too high, additional amounts of water could besprayed to the granulate in order to obtain pimavanserin having theproperties desired in order to pharmaceutically manufacture capsulescomprising 5-34 mg pimavanserin. Adding too much water may alter otherproperties of the API, such as its crystallinity. The properties areachieved via a manufacturing process that includes granulation, using asuitable granulator, e.g. a high shear granulator, simultaneouslyspraying the adequate amount of water while mixing, followed byscreening, and blending appropriate quantities of excipients. In someembodiments the lack of a binder, and using pimavanserin, properlywetted and not over-wetted are believed to be reasons for the filluniformity observed using the herein described manufacturing process.Over-wetted granulation could seriously affect the further processing.In some embodiments particle size distribution of the granulatedpimavanserin is controlled and matched to the particle size distributionof the diluents and other excipients to minimize segregation and improveflow and capsule filling reproducibility. The particle size distributionis also considered a factor involved in the successful filing ofcapsules of size 3 or 4, as a too aggressive milling would cause a widerparticle size distribution and hamper the encapsulation. Examples ofsuitable particles size distribution of the granulated pimavanserin is aparticle size distribution (D90) of 60-450 μm, such as 100-420 μm, suchas above 250 μam. Particle size distribution referred to herein isobtained using Laser light scattering particle size (LLS PS) analyses ofgranulated pimavanserin conducted on a Malvern Mastersizer 2000 LLS PSsystem using a Scirocco 2000 dry dispersion unit using standard non-GMPconditions, and in a sample size of about 2-10 g. Suitable diluents suchas microcrystalline cellulose, silicified microcrystalline cellulose,low substituted hydroxylpropyl cellulose or similar materials to aconcentration approximately one-half of the granulation and lubricatedwith magnesium stearate, sodium stearyl fumarate or other suitablelubricants to prevent sticking to the encapsulation tooling. In someembodiments the particle size distribution of the diluent is matched tothe above mentioned particle size distribution of granulatedpimavanserin, for example microcrystalline cellulose having a particlesize distribution (D90) is 180-420 μm, such as above 250 μm. In someembodiments the lubricant, such as magnesium stearate is also matched tothe API. In some embodiments the matching of the particle sizedistribution of the lubricant, compared to the diluent, is lessimportant in view of the lower amounts used in some embodiments.Optionally suitable binders and/or disintegrants may be included in theblending of the pimavanserin granulation. In some embodimentspimavanserin is blended with a diluent, e.g. microcrystalline celluloseand lubricant, magnesium stearate only, whereas amounts of water wereadded by spraying during the granulation process

In some embodiments the particle size distribution (D90) of thecomposition is 60-380 μm, such as 75-350 μm, such as 100-300 μm.

FIG. 4 discloses the particle size distribution of pimavanserintartrate, prior to the herein disclosed granulation process.

FIG. 5 discloses the particle size distribution of the granulatedpimavanserin. The arrow in FIG. 5 indicates the area of particles sizedistribution of the API. A substantial change in the particle sizedistribution can be seen, e.g. the D90 has increased from about 30 μmfor the API to above 279 μm.

The matching of particles size distribution of the API and diluent isconsidered one factor influencing the herein disclosed robust processand reproducible encapsulation of pimavanserin, e.g. 10-34 mg pimavansemin size 4 capsules, e.g. two-piece capsules.

In some embodiment bulk density between the API and the diluent andoptionally the lubricant are matched, for example granulatedpimavanserin having a bulk density above >0.40 g/ml, such as about 0.5g/ml, and the diluent 0.35-0.46 g/ml.

In some embodiments both the bulk density and the particle sizedistribution is used in combination in order to adequately match atleast the pimavanserin granulate and the diluent in order to obtaincapsules of size 4 comprising 10-34 mg pimavanserin.

In some particular embodiments the granulation of pimavanserin may becompleted and the obtained pimavanserin granulation having suitableproperties for the herein disclosed manufacturing process, in theabsence of a binder. It is however possible to include a binder in thegranulation but for various reasons not necessarily preferred.

In some embodiments disclosed herein the blended pimavanserincomposition, as described herein, comprised in a capsule (e.g a size 4capsule) have an average Specific Energy (SE) of less than 5 mJ/g, suchas less than 4.5 mJ/g, such as less than 4 mJ/g, as obtained by FT4measurement.

In some embodiments disclosed herein the blended pimavanserincomposition, as described herein, comprised in a capsule (e.g a size 4capsule) have an average Flow Rate Index (FRI) of 0.9-1.2, such as1.0-1.1, as obtained by FT4 measurement.

In some embodiments disclosed herein the blended pimavanserincomposition, as described herein, comprised in a capsule (e.g a size 4capsule) have an average Specific Energy (SE) of less than 4.5 mJ/g, andan average Flow Rate Index (FRI) of 0.9-1.2.

Pharmaceutical Formulations

Some embodiments include a pharmaceutical composition comprisinggranulated pimavanserin tartrate, Form C which may include a smallpercentage of Form A, including a pharmaceutically acceptable diluent,binder or excipient, or combination thereof.

The pharmaceutical compositions disclosed herein, are in someembodiments, provided as a two-piece hard shell capsules made of gelatin(fish, mammalian, or vegetable sourced) or other combinations. Thetwo-piece hard shell capsules may contain the pimavanserin granules witha filler/diluent and/or lubricants.

The finished dosage forms may be presented in packaging containing metalor plastic foil such as a blister pack. The pack may also be accompaniedwith a notice associated with the container in form prescribed by agovernmental agency regulating the manufacture, use, or sale ofpharmaceuticals, which notice is reflective of approval by the agency ofthe form of the drug for human or veterinary administration. Suchnotice, for example, may be the labeling approved by the U.S. Food andDrug Administration for prescription of drugs, or the approved packageinsert.

WO 2007/133802 discloses that only certain components are compatiblewith pimavanserin, and although certain components are compatible theiruse in the herein disclosed capsule may not be preferred. A particularexample is lactose as it may have implications to the administration tosubject being lactose intolerant.

Some requirements of the pharmaceutical manufacturing for pimavanserinare commercial operational speed, as well as stringent regulatoryrequirements. For example, the encapsulation equipment used is capableof 100,000 capsules per hour, such as 40,000-90,000 capsules per hour,such as 60,000-86,000 capsules per hour, such as 60,000-70,000 capsulesper hour. The manufacturing must be reproducible and robust to becapable of this output while producing quality product.

Prior to the surprising finding, i.e. the herein disclosed processes andcompositions resulting in a robust and reliable filling of 5-34 mgpimavanserin in capsules of size 3 or 4, such as size 4 capsules, manyexperiments were done.

Comparative Experiments Resulting in Unacceptable Products

For example, the pharmaceutical industry has used fluid-bed layeringextensively for several decades to produce small spherical particleswith improved properties (e.g. flowability and compressibility) forfurther downstream processing, such as capsule filling. During thistwo-phase process that includes simultaneous spraying and drying, theaddition of a binder causes primary particles to increase the diameterof the substrate by the addition of a dense layer of the drug and abinder, one such technique evaluated was top spray layering (use ofconventional top-spray fluidized bed granulation equipment to apply thedruyg layer to a small substrate particle), e.g. using the followingcompostion about 63% w/w microcrystalline cellulose (the sphericalparticle (bead) around which the API is layered or applied), about 28%w/w of pimavanserin tartrate (API), about 6% w/w povidone (binder), suchas povidone K30, and about 2% w/w HPMC E5 (Methocel™ mE5)(hydroxypropylmethyl cellulose). The top spray fluid-bed layeringresulted resulted in particles having an acceptable flow and bulkdensity but unacceptable stability and particle size distribution aswell an an unacceptable amount of impurities. These unacceptabledisadvantages, such as unacceptable stability, less favourabledissolution, resulted in deeming this process option unsuitable for thecurrent purpose.

Wurster Layering (a similar and more common process to the Top SprayLayering described above) was tested and found to produce particleshaving an acceptable flow and bulk density but unacceptable stabilityand particle size distribution as well an an unacceptable amount ofimpurities. These unacceptable disadvantages, such as unacceptablestability, less favourable dissolution, resulted in deeming this processoption unsuitable for the current purpose. One compostion tested was thesame as in the top spray layering.

Extrusion/spheronization is especially useful in producingsemi-spherical, dense granules. The physical advantages ofextrusion/spheronization vs. other multiparticulate approaches caninclude relatively high drug loading, improved flow properties, narrowparticle size distribution, smooth and a coatable surface, lowfriability, and uniform packing characteristics. The process consists offive operations, i.e. wet granulating the formulation, followed byscreening to form cylindrical extrudates, adding the extrudate to aspheronizer forming spheres from the extrudate, and drying the spheres.Optionally coatings may be applied to the spheres. A compositioncontaining about 27% w/w pimavanserin tartrate as a 32% w/w slurry inwater, about 68% w/w microcrystalline cellulose (e.g. Avicel PH 101),about 4% hydroxypropylmethyl cellulose (e.g. Methocel™ A15LV), and about1% w/w povidone (e.g. povidone K30) resulted in particles having anacceptable flow and bulk density but unacceptable stability and particlesize distribution as well an an unacceptable amount of impurities. Theparticles were milled in order to achieve a uniform particle size, yetthe amount of impurities and stability were found to be unacceptable.

Twin-Screw Melt Granulation has increased in popularity inpharmaceutical manufacturing due to the numerous advantages of thiscontinuous manufacturing technique over traditional batch wetgranulation. Twin-Screw Melt Granulation does not require the use oforganic or aqueous solvents, making the entire process less consuming interms of time and energy as compared to wet granulation, and in view ofother tests disclosed hereinabove the use of solvent was deemed as apotential source for the impurities and may have been a factor for thestability issues observed. Consequently Twin-Screw Melt Granulation wasevaluated using a binder/disintegrant, heat and agitation. Asbinder/disintegrant a low substituted hydroxypropyl cellulose (e.g.LH-B1 marketed by Shin Etsu), and Kollidon® VA64 marketed by BASF wereused in separate compositions using about 50 w/w pimavanserin tartrateand LH-B1 and Kollidon VA64 respectively. In either case the resultingparticles were screened and evaluated resulting in particles having anacceptable flow and bulk density but unacceptable finding of impuritiesas well as unacceptable dissolution.

Conventionally wet granulation (both high shear and low shear) have beenused for a long time in pharmaceutical manufacturing, an example of aconventional wet granulation process is described in WO009/061909wherein table 7 discloses 40-50 w/w of water being used in the wetgranulation, i.e. conventionally a wet granulation uses a liquid, e.g.water in order to prepare a wet mass with sufficient plasticity whichcan be subsequently wet-milled and dried produce granules with improvedflow and density properties. High shear granulation was chosen forevaluation due to the higher energy it is capable of imparting to theparticles, which was known to improve the particle density, spherocity,and consequently the capsule filling capability and particle flow,respectively. The quantity of water used in conventional or traditionalwet granulation proved to be problematic resulting in very large, wet,adhesive pimavanserin granules that would not be easily dried in a fluidbed dryer. Additionally, large quantity of water would also result inhigh impurities and changes in the crystallinity of pimavanserin.

Several embodiments were evaluated using excipients commonly used tomitigate the impact of high water content while providing excellentgranule properties. These did not improve the resulting over-wetting ofthe pimavanserin blend and resulted in an adhesive wet mass that wouldnot would not be easily dried in a fluid bed dryer.

Contrary to the above disclosed comparative experiments the presentapplication describes processes to manufacture capsules of size 4comprising 5-34 mg pimavanserin. As additionally disclosed above it wassurprisingly found that a 100% pimavanserin high-shear granulation waspossible by using only small water quantities, often large quantities ofwater and a binder conventionally used in high-shear granulation. Inorder for a small quantity of water to be effective, the distribution ofthe water should be finely divided providing small points of localizedwetting of pimavanserin. Localized wetting is considered wetting of animmediate area around the water droplets. Examples of suitable size ofthe water droplets to be sprayed are about 0.05-0.15 mm. The granulationof pimavanserin, for example without the presence of a binder, wasachieved using a small amount of water and a nozzle, such as anatomizing nozzle, capable of producing a spray pattern that covered alarge area of pimavanserin and preventing over-wetting of large areas ofthe batch. Suitable nozzles are commercially available, e.g. fromSpraying Systems Co. Spraying of low amounts of water and appropriateimpeller speed and chopper speed of the high shear granulator achievedpimavanserin granulation having altered properties and improved theflow, e.g. bulk density compared to the native API. The total quantityof water added to the pimavanserin granulation should be limited to aglobal value the would not result in a global state of over-wetting(global refers to a large area of the batch being over-wetted), which asdescribed above would occur during conventional wet granulation ofpimavanserin, causing an adhesive wet mass that would not be easilydried in a fluid bed dryer, i.e. not resulting in a sufficiently driedproduct, or too long drying times, and increasing the risk of changingthe crystalline form of pimavanserin (e.g. changing pimavanserin intoamorphous forms), which could result in slow dissolution whenadministered to a patient. As disclosed above conventionally high sheargranulation utilizes amounts of water that would lead to over wetting ofan API, such as pimavanserin, and the present inventors havedemonstrated that an appropriate water application, e.g. using a nozzle,capable of spraying water over a large area of the API, combined with achopper/impeller speed (e.g. by controlling amperage), results ingranulated pimavanserin having improved bulk density suitable forfilling amounts disclosed herein into capsules of size 4.

In addition to the global, or batch, over-wetting a local over-wettingmay also impair the properties of the API. One solution presented hereinrelates to applying a spray of water having a droplet size such as0.05-0.15 mm, e.g. using a nozzle spraying the water and resulting inadequate wetting, locally and globally.

Suitable drying times of the wet granulation described herein is 120min, such as 100 min, such as 80 min, such as 60 min. A drying time of60 min is preferred, e.g. in view of process efficiency etc. The globalquantity of water will vary depending on many factors such as thecapacity of the high shear granulator, loading of the high sheargranulator, the batch of pimavanserin to be granulated, surroundingenvironment, and may be controlled by impeller speed and chopper speedas well as the spray rate and spray pattern parameters (e.g. using aatomization nozzle), and the amperage (energy consumption) of thegranulator. As the high shear granulator is an “open” system and energyfrom the impeller actually incorporates into the product causing theproduct temperature to increase favorably limiting the global impact ofthe added water when applied at a low rate. However, the range of waterwas found to be approximately 3-15% w/w, such as 3 -10% w/w, such as3-8% w/w (based on the mass of the pimavanserin in the granulator at thestart of the granulation process). As disclosed herein it has beendemonstrated that pimavanserin can be granulated without the use of abinder, i.e. utilizing water only. It is however contemplated that insome embodiments suitable binders, such as cellulose, methyl cellulose,polyvinylpyrrolidone and polyethylene glycol may be used, although not anecessity. The present high shear granulation of pimavanserin utilizinge.g. 3-8% w/w water, applied by an nozzle, which can generate anatomized spray pattern, provides benefits.

Embodiments disclosed herein relate to pimavanserin tartrate ascrystalline Form C, Form A or a combination thereof.

The doses referred to herein, i.e. 5-34 mg refers to pimavanserin freebase (equivalent to about 6 mg-40 mg pimavanserin tartrate).

Some embodiments relates to pimavanserin tartrate Form C (40 mg ofpimavanserin tartrate, equivalent to 34 mg pimavanserin free base) beingencapsulated in capsules of size 3 or 4, such as capsules of size 4.

One embodiment of the compositions described herein includespimavanserin tartrate granulation without binder, dried, and thereafterblended with less than 60% w/w microcrystalline cellulose such as AvicelPH302 or equivalent microcrystalline cellulose, and about 1% w/wmagnesium stearate.

In some embodiments the compositions described herein comprisesgranulated pimavanserin and microcrystalline cellulose is at least 20%w/w microcrystalline cellulose, such as 30% w/w microcrystallinecellulose, such as 40% w/w microcrystalline cellulose, such as 50% w/wmicrocrystalline cellulose, such as 50-89% w/w microcrystallinecellulose, such as 20-94% w/w, such as 50-94% w/w, such as 57-94% w/w,such as 57-89% w/w microcrystalline cellulose, such as 57-79% w/wmicrocrystalline cellulose, or 57-60% w/w microcrystalline cellulose, or57-59.5% w/w microcrystalline cellulose, or 58.5-59.5% w/wmicrocrystalline cellulose, or 59% w/w microcrystalline cellulose.

In some embodiments the compositions described herein comprisesgranulated pimavanserin and microcrystalline cellulose and magnesiumstearate, such as 0.1-3% w/w, such as 0.5-2% w/w magnesium stearate, or0.5-1.5% w/w magnesium stearate, or 1% w/w magnesium stearate.

In some embodiments the compositions described herein comprisesgranulated pimavanserin (5, 10, 20 or 34 mg) and microcrystallinecellulose is at least 20% w/w microcrystalline cellulose, such as 30%w/w microcrystalline cellulose, such as 40% w/w microcrystallinecellulose, such as 50% w/w microcrystalline cellulose, such as 50-89%w/w microcrystalline cellulose, such as 20-94% w/w, such as 50-94% w/w,such as 57-94% w/w, such as 57-89% w/w microcrystalline cellulose, suchas 57-79% w/w microcrystalline cellulose, or 57-60% w/w microcrystallinecellulose, or 57-59.5% w/w microcrystalline cellulose, or 58.5-59.5% w/wmicrocrystalline cellulose, or 59% w/w microcrystalline cellulose andmagnesium stearate, such as 0.1-3% w/w, such as 0.5-2% w/w magnesiumstearate, or 0.5-1.5% w/w magnesium stearate, or 1% w/w magnesiumstearate.

The compositions disclosed herein comprise pimavanserin and additionalcompatible excipients, e.g. sugars, sucrose, mannitol, sorbitol,polysaccharides (e.g. from corn, wheat, rice, potato), as well aspregelatinized or partially pregelatinized starches (e.g. STARCH 1500),cellulose preparations such as microcrystalline cellulose (MCC) (e.g.AVICEL® PH 302, AVICEL®PH 102, VIVAPUR® 302, VIVAPUR® 102, EMCOCEL® HD90), silicified microcrystalline cellulose (e.g. PROSOLV® 50, PROSOLV®90, PROSOLV® HD90), lactose cellulose blends (e.g. CELLATOSE® 80,CELLATOSE® 90, PROSOLV® EASYtab SP), hydroxypropylmethyl cellulose,hydroxymethyl cellulose, polyvinylpyrrolidone, lubricants such asmagnesium stearate, sodium stearyl fumarate, colloidal silicon dioxide,and talc.

Several tests attempting to mitigate the impact of the high waterquantity used in high-shear granulation by the use of excipientsgenerally capable of absorption of the water were made. However, theseproved to be unsuccessful.

One embodiment of the compositions described herein includespimavanserin tartrate granulation without binder, drying, and blendingsaid granulation with microcrystalline cellulose having a bulk densityof 0.35-0.46 g/ml, and wherein the bulk density of the blendedcomposition is >0.4 g/ml, such as >0.5 g/ml.

In some embodiments the composition comprises microcrystalline cellulose(MCC) having a bulk density of about 0.40 g/ml, such as 0.3-0.5 g/ml,such as 0.35-0.46 g/ml. In some embodiment the API having a bulk densityof >0.40 g/ml and MCC having a bulk density of 0.30-0.50 g/ml and isblended with magnesium stearate in order to make up a composition havinga bulk density of 0.40-0.55 g/ml.

One embodiment of the compositions described herein includespimavanserin tartrate granulation with spraying water and without anybinder, followed by, drying, and blending said granulation with lessthan 50% w/w microcrystalline cellulose such as Avicel PH302 orequivalent microcrystalline cellulose, and about 1% w/w magnesiumstearate. The spraying of water to pimavanserin tartrate is done whilemixing in an appropriate granulator.

Another embodiment of the composition described above includespimavanserin tartrate granulation containing less than 10% w/w AvicelPH302 and colloidal silicon dioxide, e.g. Aerosil Pharma 200manufactured by Evonik, with a specific surface area from about 175 toabout 225 m²/g blended with less than 60% w/w microcrystallinecellulose, such as Avicel PH302 or equivalent microcrystallinecellulose, and about 1% w/w magnesium stearate.

Another embodiment of the composition described above includespimavanserin tartrate granulation containing less than 10% w/w AvicelPH101 and colloidal silicon dioxide with a specific surface area fromabout 175 to about 225 m²/g, e.g. Aerosil Pharma 200 manufactured byEvonik, blended with less than 60% w/w microcrystalline cellulose, suchas Avicel PH302 or equivalent thereof, and about 1% w/w magnesiumstearate.

As used herein, whenever a USP is referred to it is the current officialversion at the time of filing of the application, i.e 40-NF 35, releasedNov. 1, 2016 and official May 1, 2017.

Provided herein are embodiment for manufacturing pimavanseringranulation comprising: providing pimavanserin and adding water whilemixing in an appropriate granulator, such as a high shear granulator;granulating and; drying the wet pimavanserin granulation, sizing thepimavanserin granulation, e.g. through a screen, such as a 10-20 meshscreen; and obtaining pimavanserin granulation. Said pimavanseringranulation being suitable for encapsulation in size 4 capsules, forexample by blending with a diluent before capsule filling(encapsulation).

Provided herein are embodiment for manufacturing pimavanseringranulation by: providing pimavanserin (weighed and the loss-on-drying(LOD) moisture content determined) to a high shear granulator;pre-blending (optional); providing granulation water, e.g. 3-8% w/w,e.g. by spraying at a controlled rate and/or a controlled pattern (e.g.using an atomization nozzle) while monitoring the impeller speed and/oramperage, and granulating; stopping the provision of granulation water,e.g. when the impeller amperage increases; wet massing, e.g. withoutchanging the impeller speed; drying the wet granulation, e.g. in a fluidbed dryer until the LOD moisture is at or below the LOD moisture of thepimavanserin as provided; and sizing, e.g. through a 10-mesh screen; andobtaining pimavanserin granulation. Said pimavanserin granulation beingsuitable for encapsulation in size 3 or 4 capsules, for example byproviding additional excipients during the screening, followed byfilling of the capsule.

It is important to control the amount of water, the water applicationrate and/or water application method thereof (e.g. using an atomizationnozzle, or another suitable spraying device) as too much water may havea negative impact, e.g. change its properties, such as itscrystallinity, of pimavanserin. Adding too much water, e.g. 25% w/w,would have undesired effects on properties of pimavanserin, which wouldcause issues with the continued pharmaceutical manufacturing ofcapsules. In some embodiments water is sprayed (e.g. using anatomization nozzle) to pimavanserin while mixing. Addition of waterwithout mixing may lead to localized over-wetting. Provided herein areembodiments wherein pimavanserin, for example pimavanserin tartrate,such as pimavanserin tartrate Form C, is granulated with water usinghigh shear granulation. In some embodiments the amount of water is 1-10%w/w (water based on dry ingredient content), such as 3-8% w/w. In someembodiments the impeller speed and/or chopper speed of the high sheargranulator is controlled in order to obtain a granulation of sufficientquality for further processing. The wet granulation is then dried, e.g.in fluid bed dryers or tray dryers at controlled conditions oftemperature and drying air flow. The dried granulation is then sizedusing a screening mill or other appropriate milling (delumping), andblended with appropriate pharmaceutical diluents and/or binders, such asmicrocrystalline cellulose, enabling the filling of 5-34 mg granulatedpimavanserin (equivalent to about 6 mg-40 mg pimavanserin tartrate) in asize 3 (0.30 ml volume) or 4 (0.21 ml volume) capsule. Some embodimentsrelates to the capsule being a capsule of size 4, and a two-piececapsule.

Provided herein is a process for manufacturing capsules containing 5-34mg pimavanserin; by providing pimavanserin, for example pimavanserintartrate, such as pimavanserin tartrate Form C and water, e.g. 1-10%w/w, such as 2-9% w/w, such as 3-8% w/w, such as 4-8% w/w, such as 5-8%w/w, such as 5-7% w/w to a high shear granulator, granulatingpimavanserin and the water, drying the pimavanserin granulation, sizing(or screening, may also be referred to as delumping) the driedpimavanserin granulation, e.g. using a screening mill, blending with oneor more pharmaceutical excipients, such as one or more filler (diluent)filling a size 3 or 4 capsule, e.g. a two-piece capsule, withpimavanserin granulation. Provided herein is a process for manufacturingcapsules containing 5-34 mg pimavanserin, wherein the process comprisesthe following (e.g. in said order): providing pimavanserin, for examplepimavanserin tartrate, such as pimavanserin tartrate Form C to a highshear granulator, granulating pimavanserin together with water (e.g.1-10 w/w, such as 2-9% w/w, such as 3-8% w/w, such as 4-8% w/w, such as5-8% w/w, such as 5-7% w/w) while controlling the water applicationrate, and/or atomization parameters (e.g. by using an appropriate nozzlesuch as an externally mixed, two-fluid, air-atomizing spray nozzle),impeller speed (e.g. by monitoring amperage), and/or chopper speed (e.g.by monitoring amperage), drying the granulated pimavanserin, e.g. usingfluid bed drying, sizing the dried pimavanserin granulation, e.g. usinga screening mill or other appropriate milling device (such asoscillating mills, impact mills), blending the sized pimavanseringranulation with one or more filler/diluent (optionally including alubricant), and final blending with a lubricant (unless thefiller/diluent includes a lubricant), filling a size 3 or 4 two-piececapsule with the blended pimavanserin composition. In some embodimentsthe capsule is a capsule of size 4 and the amount of pimavanserin is 34mg. As specified herein, such as hereinbelow, excipients such asdiluents, binders, lubricants, pharmaceutical flow agents, and/or otherexcipients compatible with pimavanserin may be included. Someembodiments provide pimavanserin, microcrystalline cellulose andmagnesium stearate only. Some embodiments relate to the microcrystallinecellulose having a a particle size distribution (D90) of 180-340 μm.Some embodiments relate to microcrystalline cellulose having a bulkdensity above>0.40 g/ml. Some embodiments relate to the microcrystallinecellulose having a a particle size distribution (D90) of 180-340 μm anda bulk density above>0.40 g/ml.

Provided herein are embodiments wherein the capsule is a capsule of size4, e.g. a two-piece capsule, such as a two-piece hard shell capsule,e.g. a two-piece capsule of gelatin or hydroxypropyl methylcellulose(HPMC). Some commercial examples are VCaps®, VCaps® Plus, Coni-Snap®marketed by Capsugel.

Provided are also embodiments wherein pimavanserin (granulated),microcrystalline cellulose, for example Avicel PH302 or an equivalentmicrocrystalline cellulose, and/or magnesium stearate, for examplevegetable grade are encapsulated in a capsule of size 4, for example atwo-piece capsule.

Provided are also embodiments wherein 34 mg pimavanserin (granulated)(equivalent to 40 mg pimavanserin tartrate), microcrystalline cellulose,such as microcrystalline cellulose having a particle size distribution(D90) of 180-340 μm, for example Avicel PH302 or an equivalentmicrocrystalline cellulose, and/or magnesium stearate, for examplevegetable grade are encapsulated in a capsule of size 4, for example atwo-piece capsule.

Provided are also embodiments wherein 10 or 20 mg pimavanserin(granulated), microcrystalline cellulose, for example Avicel PH302 or anequivalent microcrystalline cellulose, and/or magnesium stearate, forexample vegetable grade are encapsulated in a capsule of size 4, forexample a two-piece capsule.

Provided are also embodiments wherein 34 mg pimavanserin (granulated),59 mg microcrystalline cellulose, for example Avicel PH302 or anequivalent microcrystalline cellulose, and/or 1 mg magnesium stearate,for example vegetable grade are encapsulated in a capsule of size 4, forexample a two-piece capsule. No other excipients were added.

Also provided is a pharmaceutical composition, comprising a capsule ofpimavanserin and one or more pharmaceutically acceptable excipient(s) asprovided herein, wherein the composition is formulated such that atleast 80% of pimavanserin is released in 30 minutes upon administrationto a subject.

Also provided is a pharmaceutical composition, comprising a capsule ofpimavanserin and one or more pharmaceutically acceptable excipient(s) asprovided herein, wherein the composition is formulated such that atleast 80% of the pimavanserin is released from the composition within 30minutes upon in vitro dissolution testing according to USP<711>(apparatus 1 (basket apparatus)).

The final moisture content of the pimavanserin granulation is equivalentto the starting moisture content of the pimavanserin.

Another requirement achieved by the pimavanserin capsules disclosedherein can be a long shelf-life, i.e., a shelf-life of at least 1 yearis obtained, such as 2 years of shelf-life.

EXAMPLES

Manufacturing of a capsule, size 4 two-piece capsule, comprising 34 mgpimavanserin equivalent to 40 mg pimavanserin tartrate

Pimavanserin 34 mg capsules may be prepared as outline herein below.

Granulation: The required ingredients for all operations of the entireprocess are weighed. The loss-on-drying (LOD) moisture content of thepimavanserin is determined, for example using an appropriate LODinstrument such as those manufacture by Mettler, Arizona Instruments,Ohaus or Denver Insruments. Drying end point may be determined usingtemperature, time or weight loss. Pimavanserin is charged through ascreen (25-40 mesh) into a high shear granulator, for example a GlattPowerex 50 liter high shear granulator equipped with a 25 liter bowl.Following a pre-blend in the high shear granulator (200-400 rpm),granulation water, e.g. 5-8% w/w is sprayed at a controlled rate((18.5-26.5 g/min) at 15 psi (10.0-20.0) atomization air pressure whilemonitoring the impeller speed ((200-400 rpm)) and amperage, chopperspeed (1600-2000 rpm). When the impeller amperage increases (such as13-18%,), the spray of water is stopped and the mixture wet massing for5 minutes without changing the impeller or chopper speeds. Following the5-minute wet massing, the wet granulation is discharged and placed in afluid bed dryer (100-140 cfm; 45-55° C.); dew point 10° C.; filtershaking 15 sec/5 sec (interval/duration) until the LOD moisture is at orbelow the LOD moisture of the pimavanserin at dispensing. The driedgranulation is discharged from the fluid bed dryer, screened through ascreen (4-12 mesh), and packaged until diluent blending andencapsulation.

Diluent Blending: The screened, dried pimavanserin granulation isdispensed (weighed) for blending/encapsulation unit operations. Therequired diluent and lubricant quantities are also dispensed. Thedispensing is followed by delumping of pimavanserin granulation with ascreening mill such as 197S or U10 Comil equipped with a screen (4-12mesh) at 2300-2500 rpm, blending of the granulation with diluent using abin type blender such as 2 liter TOTE blender 20 minutes at 19-21 rpm orother appropriate blender, final blending with lubricant using the samebin type blender or other appropriate blender (3 minutes at 19-21 rpm),and encapsulation using a IIM 2100 equipped with size 4 change parts and5-12 mm dosing disk (50-90 segments per minute (spm)).

Optionally low shear granulation such as a V-Blender equipped with anintensifier bar, twin screw granulation, may be used instead of thegranulation equipment specified above wih appropriate adjustment to themilling/screening parameters to manufacture capsules of pimavanserin

Pimavanserin hard shell capsules (34 mg pimavanserin, equivalent to 40mg pimavanserin tartrate) were manufactured. Table 2 contains an exampleof a suitable formulation.

As an alternative, the herein disclosed pimavanserin granulation may becompressed as a tablet.

As an alternative, the herein disclosed pimavanserin granulations may becompressed as a tablet without futher excipients. Thus the compositiondisclosed in table 2 in some embodiments is used to form tablets. Saidtablets may be formed as an alternative to the filling of a capsule.Consequently the obtained pimavansering granulation may be compressedinto a tablet of a weight of about 100 mg.

TABLE 2 Composition of Pimavanserin granulation (34 mg) Ingredients Qty(% w/w) Qty (mg)/dose Pimavanserin Tartrate 40.0 40.0^(a)Microcrystalline Cellulose 59.0 59.0 (Avicel PH302, NF, EP) MagnesiumStearate 1.0 1.0 (Vegetable Source, USP, EP) Total 100.0 100.0 ^(a)40 mgpimavanserin tartrate salt is equivalent to 34 mg pimavanserin free base

Table 3 contains the manufacturing process equipment for pimavanserincapsules, 34 mg.

TABLE 3 Equipment class, Process Step sub-class Manufacturer, model,size Screening I (API) Hand screen 30 Mesh hand screen GranulationVertical Glatt/Powrex VG-50M granulator with 25 L Bowl Fluid Bed DryingFluid bed Glatt GPCG-5 with 25 L bowl Screening II Hand screen 10 Meshhand screen (granulation) Milling Screening mills, Comil 197S or U10with rotating impeller 045R03125 screen Blending I Diffusion mixers TOTEBin blender, (Tumble), bin 2 cubic foot blender Screening III Handscreen 30 Mesh hand screen (Magnesium stearate) Final Blending Diffusionmixers TOTE Bin blender, 2 cubic foot (Tumble), bin blenderEncapsulation Encapsulator, IIM 2100, Size 4 change parts dosing diskand 10 mm dosing disk Polishing and Not applicable Bosch KKE 1500 weightchecking

Table 4 outlines the process parameters and ranges for pimavanserincapsules, 34 mg manufacture. Bold references are target values with theranges displayed in parenthesis.

TABLE 4 Process Step: Equipment Process Parameter Ranges Screening I(API) Screen size 25-40 Mesh hand screen 25-40 Mesh hand screenGranulation Spray rate (10-50) [g/min] Glatt/Powrex VG-50M Impellerspeed (200-400) [rpm] with 25 L bowl Chopper speed (1600-2000) [rpm]Atomization (3-20) [psig] Air Pressure Fluid Bed Drying Process Air(90-210) [cfm] Glatt GPCG-5 with Volume 25 L bowl Inlet Air (40-60) [°C.] Temperature Screening II Screen size  4-12 Mesh hand screen(granulation) 4-12 Mesh hand screen Screening Screen size 25-40 meshBlending I Diffusion blender Screening Screen size 25-40 Mesh (Magnesiumstearate) Blending I Diffusion blending Encapsulation Dosing disk 5-12mm dosing disk based encapsulator

In some embodiments disclosed herein relate to pimavanserin granulation,e.g. composed as in table 2, having a weight of granulation of 100 mg±7(average of 20 samples), i.e. the weight relates to the granulationonly, i.e. excluding capsule shell weight.

The bulk density of the blended composition is >0.4 g/ml, such as0.4-0.6 g/ml, such as about 0.5 g/ml determined according to USP <616>,method 1. In some embodiments the bulk density of the compositionis >0.4 g/ml, such as about 0.5 g/ml, such as 0.51 g/ml, such as 0.508g/ml.

The bulk density of pimavanserin granulation is >0.4 g/ml, such as0.4-0.6 g/ml, such as about 0.5 g/ml, determined according to USP <616>,method 1. In some embodiments the bulk density of the pimavanseringranulation is >0.4 g/ml, such as about 0.5 g/ml, such as 0.51 g/ml,such as 0.508 g/ml.

In addition to the bulk density and Carr's Index obtained according toUSP <616>, method 1, FT4 Powder Rheology was obtained for the API(pimavanserin tartrate) and for the compositions disclosed herein usinga FT4 Powder Rheometer according to ASTM D7891-15; Standard Test Methodfor Shear Testing of Powders Using the Freeman Technology FT4 PowderRheometer Shear Cell.

As discussed herein above the flowability of the composition has beenimproved compared to the API (pimavanserin tartrate), which for examplecan be supported by the Specific Energy (SE) obtained from the FT4measurements. Specific Energy is a measure of the powder's flowabilitywhen unconfined, such as during low stress filling, or low shearblending. The average Specific Energy (SE) for the API is about10.08+/−0.23 mJ/g. The granulated pimavanserin had an average SE of6.81+/−0.63 mJ/g, and the blended pimavanserin composition an average SEof 3.96+/−0.36 mJ/g. Thus the unconfined flowability was substantiallyimproved compared to the API.

In addition to SE, the Flow Rate Index (FRI) of the composition showedsignificant improvement compared to the API (pimavanserin tartrate). FRIindicates sensitivity to changing the rate of flow, and the pimavanserintartrate had an average FRI of 1.90±0.01, the granulated pimavanserin anaverage FRI of 1.52+/−0.10, and the blended pimavanserin composition hadan average FRI of 1.08±0.06, again showing the improved properties forthe granulated pimavanserin as well as the blended pimavanserincomposition for filling into a capsule of size 3 or 4.

The FT4 Powder Rheometer was also used as yet another means to comparethe bulk density between the API, the granulated pimavanserin and theblended pimavanserin compositions disclosed herein and in theaccompanying claims. The bulk density is a conditioned bulk density asobtained by the FT4 measurement, in accordance with ASTM D7891-15;Standard Test Method for Shear Testing of Powders Using the FreemanTechnology FT4 Powder Rheometer Shear Cell. Pimavanserin tartrate (API)had an average conditioned bulk density (CBD) of 0.336±0.006 g/ml,granulated pimavanserin tartrate had an average conditioned bulk density(CBD) of 0.478±0.028 g/ml, and the blended pimavanserin composition anaverage CBD of 0.504±0.020 g/ml.

The conditioned bulk density of the blended composition is >0.45 g/ml,such as 0.45-0.6 g/ml, such as 0.47-0.55 g/ml determined according toASTM D7891-15. In some embodiments the bulk density of thecomposition >0.45 g/ml, such as an average of about 0.5 g/ml.

The conditioned bulk density of the granulated pimavanserin is >0.42g/ml, such as 0.42-0.55 g/ml, such as 0.43-0.53 g/ml determinedaccording to ASTM D7891-15. In some embodiments the bulk density of thegranulated pimavanserin >0.42 g/ml, such as an average of about 0.48g/ml.

The blended pimavanserin composition used in the herein mention FT4Powder Rheometry measurements comprised 34 mg pimavanserin, 59 mgmicrocrystalline cellulose and 1 mg magnesium stearate.

The capsules comprising 5-34 mg pimavanserin are stable upon actual orsimulated storage under open conditions at 25° C.±2°/60%±5% (RH)relative humidity for at least 1 year, such as at least 1.5 years.

Alternative methods and equipment to be used in connection with theherein disclosed methods, compostions, capsules, tablets and disclosuresmay be found in SUPAC: manufacturing equipment addendum, an U.S.Department of Health and Human Services, Food and Drug Administration,Center for Drug Evaluation and Research (CDER) issued guidance forindustry, e.g. in the December 2014 version, Pharmaceutical Quality/CMC.

The embodiments disclosed herein above meet all specifications outlinedrelating to the marketing authorization of Nuplazid®, for example:

Assay (90.0-110.0% of Label Claim), i.e. quantify the amount ofpimavanserin free base in the drug product, for example using reversephase HPLC with UV-detection at 210 nm. An example of eluent is agradient comprised of two mobile phases such as ammonium buffer (pH9.0), and acetonitrile/methanol (80/20 vol/vol).

Content Uniformity as determined using USP <905>, Uniformity of DosageForms and wherein the maximum Acceptance Value (AV) NMT (not more than)15.0. The AV is calculated for the number of units tested; Level 1=10units; Level 2=30 units using the following: the mean Assay value forthe number of units tested Minus Either 98.5 (when the mean is less than98.5% of target assay) and 101.5 (when the mean is greater than 101.5%of target assay) times 2.4 (10 units) or 2.0 (30 units) plus thedifference bewtween the Mean and the appropriate Upper/Lower % of targetassay, using the method for hard capsules.

Dissolution USP <711>:

Stage 1: Q=80% within 30 minutes

Stage 2: Average of 12 units (Stage 1 & Stage 2) is equal to or greaterthan Q with no unit less than Q-15%

X-ray powder diffraction (XRPD) analyses on a Bruker AXS D8 Advancesystem with a Bragg-Brentano configuration using CuKα radiationconfirmed that all XRPD patterns for the granulations correspond to theXRPD patterns of the currently approved NUPLAZID 17 mg tablet(pimavanserin tartrate form C), which for example as disclosed in U.S.Pat. No. 7,732,615.

Long term stability data for capsules containing 34 mg pimavanserin, 59mg microcrystalline cellulose and 1 mg magnesium stearate at 18 monthswere determined using standard procedures such as actual or simulatedstorage under open conditions at 25° C.±2°/60%±5% (RH) relativehumidity, e.g. as outlined in WHO Technical Report Series, No. 953,2009, Annex 2, and the following observations and determinations weremade:

Appearance: unchanged at 18 months

Assay (90.0-110.0% of Label Claim): Day 8: 100±2%; 18 months: 100±2%

Total impurities: Day 0: 0.3%; 18 months: 0.3%, determined in line withAssay.

Dissolution (at 18 months): at least 80% of the pimavanserin is releasedfrom the composition within 30 minutes upon in vitro dissolution testingaccording to USP<711> (apparatus 1 (basket apparatus)).

Water content (determined in line with USP<921>, method Ia : Day 0:2.9%; 18 months: 2.9%.

1. A pharmaceutically acceptable capsule for orally delivering 34 mg ofpimavanserin to a patient, wherein the capsule has a size 3 or 4 capsuleshell that encapsulates a blended pimavanserin composition comprising:40 mg granulated pimavanserin tartrate having wherein the bulk densityof the granulated pimavanserin tartrate is 0.4 to 0.6 g/ml as determinedby USP<616>, method 1; microcrystalline cellulose having a particle sizedistribution (D90) of 180 to 340 μm; wherein the particle sizedistribution is measured using laser light scattering with a MalvernMastersizer 2000 LLS PS system, a Scirocco 2000 dry dispersion unit anda sample size of 2 to 10 g.
 2. The pharmaceutically acceptable capsuleof claim 1, wherein the capsule shell is a hard shell size 4 capsule. 3.The pharmaceutically acceptable capsule of claim 1, wherein the blendedpimavanserin composition further comprises a lubricant.
 4. Thepharmaceutically acceptable capsule of claim 3, wherein the lubricant ismagnesium stearate.
 5. A pharmaceutically acceptable capsule for orallydelivering 34 mg of pimavanserin to patient, wherein the capsule has asize 3 or 4 capsule shell that contains a blended pimavanserincomposition comprising: 40 mg granulated pimavanserin tartrate whereinthe bulk density of the granulated pimavanserin tartrate is 0.4 to 0.6g/ml as determined by USP<616>, method 1; and 57-60% w/wmicrocrystalline cellulose.
 6. The pharmaceutically acceptable capsuleof claim 5, wherein the blended pimavanserin composition furthercomprises 0.1 to 3% w/w magnesium stearate.
 7. The pharmaceuticallyacceptable capsule of claim 5, wherein the bulk density of the blendedpimavanserin composition is 0.4 to 0.6 g/ml as determined by USP <616>,method
 1. 8. The pharmaceutically acceptable capsule of claim 5, whereinthe microcrystalline cellulose has a particle size distribution (D90) of180 to 340 μm and wherein the particle size distribution is measuredusing laser light scattering with a Malvern Mastersizer 2000 LLS PSsystem, a Scirocco 2000 dry dispersion unit and a sample size of 2 to 10g.
 9. The pharmaceutically acceptable capsule of claim 5, wherein thecapsule releases at least 80% of the pimavanserin within 30 minutes inaccordance with USP <711>dissolution apparatus
 1. 10. Thepharmaceutically acceptable capsule of claim 1, wherein the capsule isstable upon actual or simulated storage under open conditions at 25°C.±2°/60%±5% relative humidity for 1 year.
 11. The pharmaceuticallyacceptable capsule of claim 5, wherein the capsule is stable upon actualor simulated storage under open conditions at 25° C.±2°/60%±5% relativehumidity for 1 year.
 12. A pharmaceutically acceptable capsule fororally delivering 34 mg of pimavanserin to patient, wherein the capsulehas a size 3 or 4 capsule shell that contains a blended pimavanserincomposition comprising: 40 mg granulated pimavanserin tartrate whereinthe bulk density of the granulated pimavanserin tartrate is 0.4 to 0.6g/ml as determined by USP<616>, method 1; a filler and a lubricant,wherein the D90 particle size distribution of the blended pimavanserincomposition is 100 to 300 μm as measured using laser scattering particlesize analysis.
 13. The pharmaceutically acceptable capsule of claim 12,wherein the capsule has a size 4 capsule shell.